This proposal addresses broad Challenge Area (15) Translational Science, and specific challenge topic 15-MH-109 Prefrontal cortex regulation of higher brain function and complex behaviors. Nearly all psychiatric disorders, from schizophrenia to depression to addiction, disrupt emotional processing. A key aspect of the pathophysiology underlying these psychiatric disorders is thought to lie in the dysfunction of the pre-frontal cortex, especially with respect to the manner by which the pre-frontal cortex regulates emotions. We focus in this proposal on the interactions between the pre-frontal cortex and the amygdala, a key coordinator of emotional behavior. This circuitry has been highlighted as being critical for controlling emotional responses. Our lab has recently shown that neurons in the primate amygdala respond differentially depending upon whether a cue predicts a reward or an aversive stimulus, with different populations of neurons preferring reward and aversive associations, respectively. More recent preliminary data indicates that this flexible representation of reinforcement contingencies can be "gated" - or updated instantly - depending upon a subject's learning and applying a rule for interpreting cues accurately. In this proposal, we will test the hypothesis that this gating of neural signals in the amygdala depends critically on input from the orbitofrontal cortex (OFC), a component of the pre-frontal cortex with strong connections to the amygdala. Our approach is to adapt methods for genetically and anatomically targeted expression of channelrhodopsin (ChR2) and halorhodopsin (NpHr) (light-activated channels that can be used to photo-activate or photo-inactivate neurons). These optogenetic techniques will be used in combination with neurophysiological and complex behavioral experiments. We will determine if the flexible physiological properties in the amygdala require pre-frontal input by selectively inactivating pre-frontal input with halorhodopsin, and we will further determine if disrupting information transmission from OFC to the amygdala impacts complex behavior. Overall, the development of these techniques promises to transform the study of pre-frontal/amygdala interactions by elucidating how pre-frontal input can regulate the responsivity of the amygdala, a key mechanism in maintaining normal adaptive emotional responses that likely becomes dysfunctional in many psychiatric disorders. PUBLIC HEALTH RELEVANCE: This proposal involves the development of optogenetic techniques for investigating how the prefrontal cortex regulates the amygdala in order to control emotional behavior. Since most psychiatric disorders, including mood and anxiety disorders, schizophrenia, and depression involve dysfunction in these neural circuits, this project promises to lay the groundwork for developing new treatments.